TUNISIA :

TOWARD A DRAFT GUIDELINE ON

BIOSIMILARS IN 2016 !
J. KHLIF, S. BEN TKHAYET, M. BEN GHORBEL, I. FRADI.
Unit of Pharmacy and Medicines (UPM)
Ministry of Health - Tunisia

Amman, 15th september 2015

1
Problem context
 International level

1 • Beyond the High Cost of biological products

• Need for biosimilars as a real hope for patients

2 (oncology)

• There was a Global development of biosimilars

3

• So different procedures were launched for biosimilars

4 registration all over the world

2
Problem context

 National level

• Pharmaceutical industries portfolio continues to grow

1

• Local biosimilars are emerging

2

• With a particularity in their process : transfer of technology

3 (a partnership with foreign referent laboratories)

• During the registration procedure, we encountered the

4 problem : Lack of a national regulation on biosimilars

3
 Problem context

Guarantee quality, efficacy and

safety

Supporting local Accelerate biosimilars

production marketing

Tunisian Biosimilars guidelines

4
 DRUG REGISTRATION IN
TUNISIA

5
Marketing authorization procedure

UPM (MoH)
Application submission

Administrative information
(Module 1)

NMCL Experts
(Module 3) (Module 4 and 5)

Specialized Scientific
Assessment and Testing Commission (SSC)

Technical Committee for

Proprietary Medicinal Products
Assessment of Drug quality (Module 3)

National Medicines Control Laboratory

 Assessment of the pharmaceutical data

 Teams of assessors (pharmacist and doctors)
 Following the International Guidelines

7
Security and efficacy assessment
(Module 4 and 5)

Experts / Specialized Scientific Commissions

(SSC)

Approximately 260 Experts appointed by The

Minister of Health from different relevant specialties

17 Specialized Scientific Commissions

Each one occurs once or twice per year

Technical Committee for Proprietary
Medicinal Products
Committee composition :
• Experts representatives of different specialties
• College of pharmacists and physicians
• Representatives of relevant governmental structures
(NMCL, DIP, NCPV, Central Pharmacy of Tunisia, National
Health Insurance Fund/ Ministry of Social Affairs, ministry of
commerce)

Global evaluation
• Quality report (NMCL)
Approval or rejection
• SSC opinion
of the MAA
• Price negotiation
 REGISTRATION OF
BIOSIMILARS IN TUNISIA

10
 In case of a biosimilar , we are applying the procedure, following :
WHO

11
FDA

12
EMA
Guideline on similar biological medicinal products
CHMP/437/04 Rev 1

Guideline on similar biological medicinal products

containing biotechnology-derived proteins as AS:
quality issuess EMA/CHMP/BWP/247713/2012 INF

Heparin

Guideline on similar biological medicinal products Insulin

containing biotechnology-derived proteins as AS :
non-clinical and clinical issues Somatropin
EPO
EMEA/CHMP/BMWP/42832/2005 Rev1
G-CSF

Guideline on immunogenicity assessment of

monoclonal
biotechnology-derived therapeutic proteins
antibodies
EMA/275542/2013
13
EMA genral and specific guidelines clarifying some requirements specially for
preclinical , clinical and immunogenicity issues
 SITUATION IN TUNISIA

14
 Filgrastim (Timeframes of MA)
INN Trade Name MAH MAA MA

FILGRASTIM NEUPOGEN AMGEN (EX-ROCHE R 1999

PHARMA SUISSE)

IOR CENTER OF MOLECULAR B 09/2004 05/2008

IMMUNOLOGY
LEUKOCIM
ZARZIO SANDOZ GMBH AUTRICHE B 10/2011 10/2012

NEUTROMAX BIO SIDUS S.A B 11/2010 12/2011

GRASTIM MEDIS (TUNISIA) B 12/2010 -

NIVESTIM HOSPIRA UK LIMITED B 04/2012 -

HEBERVITAL HEBER BIOTEC (CUBA) B 11/2012 -

15
NB: All the pending MAA are published in our website : www.dpm.tn
 Erythropoïetin
INN Trade Name MAH MAA MA

ERYTHROPOÏETIN EPREX JANSSEN-CILAG R 2010

EPOMAX MEDIS - TUNISIA B 04/2009 05/2013

HEMAX BIO SIDUS S.A B 02/2000 12/2002

Ior EPOCIM CENTER OF MOLECULAR B 07/2010

IMMUNOLOGY

EPOTIN JULPHAR B 01/2008 -

BINOCRIT SANDOZ GMBH AUTRICHE B 05/2013 -

EPOKINE MID PHARMA JORDANIE B 05/2007 -

REPOITIN SERUM INSTITUTE OF B 05/2011 -

INDIA

16
 Somatropin

INN Trade Name MAH MA

SOMATROPINE GENOTROPIN PHARMACIA AB SUEDE R 12/1993

OMNITROPE SANDOZ GmbH AUTRICHE B 05/2015

HHT BIO SIDUS S.A B 07/2009

17
Gonadotrophin

INN Trade Name MAH MAA MA

GONADOTROPHIN GONADOTROPHINE ORGANON S.A R 03/1993

GESTAL MEDIS (TUNISIA) B 01/2014 -

18
 Enoxaparin

INN Trade Name MAH MA

ENOXAPARINE LOVENOX SANOFI-AVENTIS FRANCE R 10/1990

ENOXA anti-xa/0.2ml MEDIS (TUNISIA) B 05/2007

ENOXAMED UNIMED (TUNISIA) B 01/2005

19
 Interferon beta 1a

INN Trade Name MAH MAA MA

MERCK SERONO EUROPE

INTERFERON BETA 1A REBIF Limited UK
R 06/2009

BLASTOFERON BIO SIDUS S.A B 03/2011 -

NAPFERON BETA MEDIS (TUNISIA) B 03/2015 -

20
 Insulin glargin

INN Trade Name MAH MAA MA

INSULIN LANTUS SANOFI-AVENTIS DEUTSCHLAND R 04/2003

GLARGEN MEDIS (TUNISIA) B 01/2014 -

21
Monoclonal antibodies

INN Trade Name MAH MAA MA

INFLIXIMAB REMICADE JANSSEN BIOLOGICS B.V R 03/2002 08/2003

REMSIMA HIKMA PHARMACEUTICALS B 06/2015 -

RITUXIMAB MABTHERA ROCHE PHARMA LTD R 11/2001 05/2003

SUISSE

REDITUX DR REDDY'S B 07/2014 -

TRASTUZUMAB HERCEPTIN ROCHE PHARMA LTD R 02/2005 04/2008

SUISSE

HERTRAZ MYLAN LABORATORIES B 12/2014 -

LIMITED

22
 TUNISIAN GUIDELINES FOR
BIOSIMILARS

23
 Tunisian Guidelines on Biosimilars
registration

Draft Redaction Validation Communication Adopted

Group Group seminar Guideline

24
Draft Redaction Group
Our project has started since April 2015
 first draft before 2016 :
 UPM
 NMCL
 NCPV
 Experts :
 Clinicians
 Analytical chemistry
 Biotechnology
 Pharmacology
 Clinical trials
 Pharmacovigilance

25
Draft Redaction Group

 Stakrholders (involved in the project)  take their

perspectives into account.
 Delegates of the syndicate of local manufacturers (CNIP)
 The tunisian syndicate of research and developement
laboratories (SEPHIRE : multinational laboratories)
 Investigators and clinical research associates (CRA)
experienced in biosimilarity clinical trials

26
Draft Redaction Group

 Decision : To refer to other guidelines, and not to redact

a new one  in order to benefit from the experiences of
the other countries.

 Guidelines from other countries (besides the WHO, FDA

and EMA guidelines) were benchmarked.
 ie : egyptian, jordanian guidelines ...

27
Main sections of the Guideline
the same as most of the biosimilar guidelines

Scope

Reference biotherapeutic product

Registration procedure

Quality

Non-clinical evaluation

Clinical evaluation

Pharmacovigilance

Interchangeability

Transfert of technology

28 Legal basis
 TUNISIAN GUIDELINES :
CHALLENGES

29
First Challenge
Scope

Reference biotherapeutic product

Registration procedure

Quality

Non-clinical evaluation

Clinical evaluation

Pharmacovigilance

Interchangeability

Transfert of technology

Legal basis

30
 IMPORTED biosimilars registration procedure

COMBINED MAA

EVALUATION
Preclinical
Quality & Clinical M3 SUBMISSION M4+ M5 (EXPERTS)
assessment data
assessment

M3 ASSESSMENT(NMCL) SSC

 To shorten the MA timeframes

TC
Adapt the registration procedure in
order to allow a combined
evaluation of the comparability MA
exercices :
 Quality (NMCL)
 Efficacy and security (Specialized
Scientific Commission)
 LOCALLY MANUFACTURED biosimilars registration procedure

STEPWISE APPROACH MAA

Quality assessment Fast

track M3 SUBMISSION M4 SUBMISSION
Preclinical studies
Clinical trials M3 ASSESSMENT M4 ASSESSMENT
(QUALITY) - FAST TRACK
SSC - TC
MA
PRECLINICAL
STUDY M5 SUBMISSION

 To shorten the MA timeframes

Define a « fast and wise » stepwise
CLINICAL TRIAL
approach
 we decided to implement a fast track
procedure for the quality assessment before SSC
going to the preclinical and the clinical studies
TC

32 MA
Challenges
Scope

Reference biotherapeutic product

Registration procedure

Quality

Non-clinical evaluation

Clinical evaluation

Pharmacovigilance

Interchangeability

Transfert of technology

Legal basis

33
Challenges
Quality, preclinical and clinical issues :
 The working group was splitted into 3 taskforces to
discuss the choice of the suitable guideline that would
be adopted in each section

 In some sections, most of the guidelines are in a complete

concordance.
 In others, many disparities were highlighted

34
Challenges

 Shall we choose/adopt the guidelines that are more

drastic, specially about :
 The neccessity of a clinical trial for some biosimilar classes?
 The design of the clinical trial?
 The timing of the immunogenicity assessment?
 … ???

 How to choose the reference product when it is not

registered in Tunisia and there is no access to its
pharmaceutical data to assess its quality comparability ?

35
Challenges

 Pharmacovigilance :
In Tunisia, we have already adopted a main part of the
Guideline on good pharmacovigilance practices (GVP) For
Arab Countries, since July 2015.

 The interchangeability :
In Tunisia, we follow the “call for tenders” mode to
import most of the hospital drugs  the medicine could
be substituted every one or 2 years.

36
THE BIG Challenge
Scope

Reference biotherapeutic product

Registration procedure

Quality

Non-clinical evaluation

Clinical evaluation

Pharmacovigilance

Interchangeability

Transfer of technology

Legal basis

37
THE BIG Challenge
 In case of a transfer of technology : the most frequent case for
locally manufactured biosimilars in Tunisia
 Local manufacturer has a partnership with a foreign referent
laboratory :
Same active substance

Same formulation process

Can we consider the local finished product is the

same FP already marketed as a biosimilar in the
country of the referent laboratory?
???
38
THE BIG Challenge
 Transfer of technology :
 In this case, regarding to all the published guidelines, shall we
require preclinical studies for the local biosimilar ?
 Could the partner clinical trials be sufficient to demonstrate
biosimilarity of the tunisian product ?

39
A STEPWISE or A COMBINED APPROACH???
Transfer of technology

STEPWISE APPROACH COMBINED

Quality assessment PK/PD
EVALUATION
Fast
track Preclinical
Preclinical studies OR Quality & Clinical
assessment data
Clinical trials assessment

SSC - TC
Caractérisation Analyses
MA biologique

And which approach will be applied ??

Développeme
nt du procédé

40
 PERSPECTIVES

41
Perspectives

 We have to Garantee quality, efficacy and safety of biosimilars

 Pre-marketing
 Post marketing monitoring +++
 Accelerate the marketing of biosimilars to access to patients
developed therapies with a great economic benefit

42
Economic Benefit
Cost in MD of REMICADE vs biosimilar (at least -30%)
9
8
7
1 M$
6
5
4
3
REMICADE
2
BIOSIMILAR
1
0
2012 2013 2014 estimation 2015

Cost in MD of l'HERCEPTIN vs Biosimilar (at least -30%)

45 5 M$
40
35
30
25
HERCEPTIN
20
BIOSIMILAR
15
10
5
0
43 2012 2013 2014 estimation 2015
Conclusion
 To Garantee quality, efficacy and safety of biosimilars
 Pre-marketing
 Post marketing monitoring +++
 Accelerate the marketing of biosimilars to access to patients
developed therapies with a great economic benefit

TO ESTABLISH A CLEAR REGISTRATION PROCEDURE

TOWARD A REGULATORY HARMONIZATION

44
 "The courage of the water drop is
to fall into the desert." Lao She

Thank you !
45